1. Field of the Invention
The present invention relates to a method for producing .alpha.-L-aspartyl-L-phenylalanine dimethyl ester which is an intermediate in the production of .alpha.-L-aspartyl-L-phenylalanine methyl ester and to a method for producing .alpha.-L-aspartyl-L-phenylalanine methyl ester from the dimethyl ester.
2. Description of the Background
.alpha.-L-Aspartyl-L-phenylalanine methyl ester (.alpha.-APM) is a substance that is much in demand as a novel low calorie sweetener of good quality.
For the production of .alpha.-APM, a variety of methods are already known. One method involves the condensation of N-protected-L-aspartic anhydride with L-phenylalanine methyl ester and the N-protective group is then cleaved in a conventional manner (U.S. Pat. No. 3,786,039). Another method is the direct condensation of a strong acid addition salt of L-aspartic anhydride with L-phenylalanine methyl ester (Published Examined Japanese Patent Application No. 14217/74) Still another method is the condensation of N-protected-L-aspartic acid with L-phenylalanine methyl ester in the presence of an enzyme. The N-protective group is then cleaved in a conventional manner (Published Examined Japanese Patent Application No. 135595/80).
However, .alpha.-APM tends to change to easily revert to 3-benzyl-6-carboxymethyl-2,5-diketopiperazine or, if .alpha.-APM is in a medium containing alcohol, it is partly converted into the alkyl ester (DKP or DKP derivatives), because of its physical properties. In the production of .alpha.-APM on an industrial scale, the yield of by-products is large. The problem of by-product formation is common to all of the methods for producing .alpha.-APM.
On the other hand, a method is known for producing .alpha.-APM in which a DKP or DKP derivative is brought into contact with a strong acid in a solvent mixture of methanol and water, thereby resulting in the cleavage of the amide bond (Published Unexamined Japanese Patent Application Nos. 174799/85 and 22519/86). According to the method, however, water is present in large quantities and the reaction is carried out using strong acids so that both of the peptide bonds in DKP are cleaved to the by-products: aspartic acid and phenylalanine. Further, also, in the case where one of the two peptide bonds in DKP is cleaved, the selectivity is poor and undesired phenylalanyl aspartic acid or the methyl ester thereof is produced in large quantities. A need therefore continues to exist for a method by which .alpha.-APM can be produced in improved yields from DKP with greatly reduced hydrolysis to the basic amino acid materials and undesired peptides.